USPTO Patents Application 10551504

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PATENT COOPERATION TREATY

PCT

INTERNATIONAL PRELIMINARY REPORT ON PATENTABILITY

(Chapter I of the Patent Cooperation Treaty)

(PCT Rule AAbis)

Applicant's or agent's file reference

FOR FURTHER ACTION

See item 4 below

C1-A0416Y1P

International application No.

International filing date (dav/rnonMvear)

Priority date (dav/momh/year)

PCT/J P2006/306800

31 March 2006 (31 .03.2006)

31 March 2005 (31 .03.2005)

Internationa] Patent Classification (8th edition unless older edition indicated )

See relevant information in Form PCT/lSA/237

Applicant

CHUGAI SEIYAKU KABUSHIKI KAISHA

1 . This international preliminary report on patentability (Chapter I) is issued by the International Bureau on behalf of the
International Searching Authority under Rule 44 bis. 1(a).

2. This REPORT consists of a total of 6 sheets, including this cover sheet.

In the attached sheets, any reference to the written opinion of the International Searching Authority should be read as a reference
to the international preliminary report on patentability (Chapter I) instead.

3. This report contains indications relating to the following items:

Box No.

I

Basis of the report

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Box No.

n

Priority

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Box No.

ni

Non-establishment of opinion with regard to novelty, inventive step and industrial
applicability

□

Box No.

rv

Lack of unity of invention

Box No.

V

Reasoned statement under Article 35(2) with regard to novelty, inventive step or industrial
applicability; citations and explanations supporting such statement

□

Box No.

VI

Certain documents cited

□

Box No.

vn

Certain defects in the international application

□

Box No.

vm

Certain observations on the international application

4. The International Bureau will communicate this report to designated Offices in accordance with Rules 44ij/"f.3(c) and 93bisA but
not, except where the applicant makes an express request under Article 23(2), before the expiration of 30 months from the priority
date (Rule AAbis .2).

Date of issuance of this report
03 October 2007 (03.10.2007)

The International Bureau of WIPO
34, chemin des Colombettes
121 1 Geneva 20, Switzerland

Facsimile No. +41 22 338 82 70

Authorized officer

Yoshiko Kuwahara

e-mail: pt()7.pct@wipo.int

Form PCTOB/373 (lanuary 2004)

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PATENT COOPERATION TREATY

From the

INTERNATIONAL SEARCHING AUTHORITY

Tor

PCT

WRITTEN OPINION OF THE
INTERNATIONAL SEARCHING AUTHORITY

(PCT Rule 43Ws.l>

Dale of mailing

( day/mom hfyewr)

Applicant's or agent's file reference

C1-A0416Y1P

FOR FURTHER ACTION

See paragraph 2 below

International application No.

PCT/JP2006/306800

International filing, date {day fnwixihf year)

31.03.2006

Priority date {(kty/maiith/yecir)

31.03.2005

International Patent Classification (IPO or both national classification and IPC

Applicant

CHUGAI SEIYAKU KABUSHIKI KAISHA

1. This opinion contains indications relating to the following items:
Basis of the opinion
Priority

Non-establishment of opinion with regard to noveliy, inventive slep and industrial applicability
Lack of unity of invention

Reasoned statement under Rule 4?^/sJ(a)(j) with regard to novelty, inventive step or industrial
applicability: citations and explanations supporting such statement

Certain documents cited

Certain defects in the international application
Certain observations on the international application

2. FURTHER ACTION

If a demand for international preliminary examination is made, this opinion will be considered to be a written opinion of the
International Preliminary Examining Authority ("IPEA"* except that this does not apply where the applicant chooses an Authority other
than this one to be the IPEA and the chosen IPEA has notified the Internationa] Bureau under Rule (&Abis{b) that written opinions of
this International Searching Authority will not be so considered.

If this opinion is. as provided above, considered to be a written opinion of the IPEA. the applicant is invited to submit to the IPEA a
written reply together, where appropriate, with amendments, before the expiration of 3 months from the date of mailing of Form
PCT/ISA/220 or before the expiration of 22 months from the priority date, whichever expires later.

For further options, see Form PCT/ISA/220.

3. For further details, see notes to Form PCT/ISA/220.

Name and mailing address of the ISA/.TP

Date of completion of this opinion

Authorized officer

Facsimile No.

Telephone No.

Box No. I

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Box No. II

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Box No. Ill

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Box No. IV

Box No. V

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Box No. VI

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Box No. VII

□

Box No. VIII

Form PCT/ISA/237 (cover sheet) (April 20051

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WRITTEN OPINION OF THE
INTERNATIONAL SEARCHING AUTHORITY

International application No.

PCT/JP2006/306800

Box No. I

Basis of this opinion

With regard lo the language, this opinion has been established on the basis of:
the international application in the language in which it was filed

the translation of the international application into

□

translation furnished for the purposes of international search (Rule 12.3U> and 23.1(,b>).

With regard to any nucleotide and/or amino acid sequence disclosed in the international application and necessary to Ihe claimed
invention, this opinion has been established on the basis of:

a. type of material

a sequence listing .
[ | table(s) related to the sequence listing

b. format of material
^ | on paper

pK] >n electronic form

c. lime of filing/furnishing,

contained in the international application as filed
| | filed together with the international application in electronic form
| furnished subsequently lo this Authority for Ihe purposes of search

| | In addition, in the case that more than one version or copy of a sequence listing and/or tablets) relating thereto has been filed or
furnished, the required statements that the information in the subsequent or additional copies is identical to that in the application as
filed or does not go beyond the application as filed, as appropriate, were furnished.

Additional comments:

Form PCT/ISA72?7 (Box No. I) (April 2I>05>

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WRITTEN OPINION OF THE
INTERNATIONAL SEARCHING AUTHORITY

International application No.

PCT/JP2006/306800

Box No. V Reasoned statement under Rule 43bis.l(a)(i) with regard to novelty, inventive step or industrial applicability;
citations and explanations supporting such statement

Statement

Novelty (N)

Claims 1-44
Claims

YES
NO

Inventive step (IS)

Claims

Claims 1-4 4

YES
NO

Industrial applicability (IA) Claims 1 — 4 4 YES
Claims NO

2. Citations and explanations:

Document J .

KEPRIYANOV SM. et al.. Effect of domain order on the activity of bacterially
produced bispecific single-chain Fv antibodies., J. Mol. Biol., 2003, Vol. 330, No. 1,
pages 99-1 11
Document 2.

KRIANGKUM J. et al.. Bispecific and bifunctional single chain recombinant
antibodies., Biomol. Eng., 2001, Vol. 18. No. 2, pages 31-40
Document 3:

DE JONGE J. et al.. In vivo retargeting of T cell effector function by recombinant
bispecific single chain Fv {anti-CD3 x anti-idiotype) induces long-term survival in the
murine BCL1 lymphoma model., J. Immunol., 1998, Vol. 161, No. 3, pages 1454-1461
Document 4:.

MALLENDER WD. et al.. Construction, expression, and activity of a bivalent
bispecific single-chain antibody., J. Biol. Chem.. 1994, Vol. 269, No. 1, pages 199-206
Document.^:

MACK M. et al., A small bispecific antibody construct expressed as a functional
single-chain molecule with high tumor cell cytotoxicity.. Proc. Natl. Acad. Sci. USA..
1995 , Vol. 92 , No. 15 , pages 702 1 -7025
Document 6.

ORITA, T. et al., A novel therapeutic approach for thrombocytopenia by minibody
agonist of the thrombopoietin receptor.. Blood, 15 January 2005, Vol. 105, No. 2, pages
562-566

(Continued in supplemental box)

Form PCT/ISA/237 (Box No. V) (April 2005)

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WRITTEN OPINION OF THE
INTERNATIONAL SEARCHING AUTHORITY

International application No.

PCT/JP2006/306800

Supplemental Box

In case the space in any of the preceding boxes is not sufficient.
Continuation of: &OX V . 2

•Claims 1,2, 5, 6, 8,9-12, 14-17, and 19-22

Documents 1-3 state that incorrect Fv combinations occur in bispecific sc(Fv)2
antibodies.

Documents 1-3 do not mention the intention to eliminate bispecific sc(Fv)2
antibodies formed by erroneous combinations of such VH and VL fragments
(hereinafter, "erroneous bispecific sc(Fv)2"). However, this authority finds that persons
skilled in the art will naturally recall that such an "erroneous bispecific sc(Fv)2"
antibody will lose its original antigen binding capability and should not be present
together with the original "bispecific sc(Fv)2."

This being the case, this authority finds that persons skilled in the art can easily
conceive of trying to eliminate such "erroneous bispecific sc(Fv)2" antibodies by
performing an affinity purification procedure using a bispecific antigen corresponding
to the original "bispecific sc(Fv)2" as described in document 4. hi addition, this
authority finds that persons skilled in the art can attempt to use a substance purified
thereby as a pharmaceutical composition and the like in accordance with the properties
thereof as needed.

In this context, judging from the statements in the DESCRIPTION of this
application, bispecific substances are included in the scope of the terms "sc(Fv)2,"
"single chain diabody," and "bivalent scFv" in the claims, and because the
aforementioned original "bispecific sc(Fv)2" and the "erroneous bispecific sc(Fv)2" are
related as "structural isomers" referred to in the DESCRIPTION of this application, this
authority finds that essentially performing the aforementioned affinity purification
procedure corresponds to the step wherein structural isomers in an sc(Fv)2 composition
are separated, and a specific structural isomer is acquired.

In addition, this authority finds that no particularly outstanding effect is provided
by adopting the constituent elements of the inventions of the above claims.

As a result, this authority finds that persons skilled in the art could easily arrive at
the inventions of the above claims based on the descriptions in documents 1-4, and
therefore these inventions lack an inventive step.

•Claims 3, 4, 7, 13, and 39-43

Document 1 states that when the linker connecting two scFv fragments is long, for
example 15 amino acids or longer, the likelihood that the antibody will become an
"erroneous bispecific sc(Fv)2" is increased by the flexibility of that linker. In addition,
documents 5 and 6 specifically describe linkers comprising 15 amino acids.
(Continued in supplemental box)

Form PCT/ISA/237 (Supplemental Box) (April 20115)

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WRITTEN OPINION OF THE
INTERNATIONAL SEARCHING AUTHORITY

Inlernalional application No.

PCT/JP2006/306800

Supplemental Box.

V. 2

In this context, this authority finds that persons skilled in the art familiar with these
descriptions will naturally recall adjusting the linker length so that a desired bispecific
sc(Fv)2 will be formed as much as possible.

In addition, this authority finds that no particularly outstanding effect is provided
by adopting the constituent elements of the inventions of the above claims.

As a result, this authority finds that persons skilled in the art could easily arrive at
the inventions of the above claims based on the descriptions in documents 1-6, and
therefore these inventions lack an inventive step.

•Claims 18 and 44

Figure 1A of document 3 shows that an original "bispecific sc(Fv)2 " and
"erroneous bispecific sc(Fv)2) are detected as different bands in an SDS-PAGE
procedure.

This being the case, this authority finds that persons skilled in the art will naturally
recall attempting separation based on the differences in physical properties between
original "bispecific sc(Fv)2" and "erroneous bispecific sc(Fv)2" antibodies. In addition,
this authority finds that persons skilled in the art can attempt to discover structural
differences therein from the enzymatic degradation products thereof and the like as
needed.

In addition, this authority finds that no particularly outstanding effect is provided
by adopting the constituent elements of the inventions of the above claims.

As a result, this authority finds that persons skilled in the art could easily arrive at
the inventions of the above claims based on the descriptions in documents 1-4, and
therefore these inventions lack an inventive step.

•Claims 23-38

Performing substitutions and the like in part of the amino acid sequence of a
mutually interacting protein and changing the mode of mutual interaction thereby was
widely known technology to persons skilled in the art before the priority date of this
application.

In this context, this authority finds that the structure of the variable region of the
antibody was investigated in detail before the priority date of this application, and
based on that knowledge, persons skilled in the art could perform amino acid
substitutions as needed such that as few "erroneous bispecific sc(Fv)2" antibodies as
possible will be formed.

In addition, this authority finds that no particularly outstanding effect is provided
by adopting the constituent elements of the inventions of the above claims.

As a result, this authority finds that persons skilled in the art could easily arrive at
the inventions of the above claims based on the descriptions in documents 1-6, and
therefore these inventions lack an inventive step.

Form PC'T/ISA/237 (Supplemental Box» (April 2005)